The numerous actions of cocaine are thought to be due to the ability of the stimulant to inhibit the uptake and thus enhance the effects of catecholamines. Recently, a plethora of in vivo biochemical, electrophysiological and behavioral evidence has emerged which conclude that the stimulant also produces potent effects on the serotonergic system. These studies suggest that chronic cocaine exposure causes postsynaptic supersensitivity in serotonergically-mediated receptor functions via a presynaptic deficit in serotonin. The mechanisms by which either acute or chronic cocaine exposure alters presynaptic neuronal serotonin chemistry is not yet fully understood and no in vivo study has systematically addressed the issue. Serotonergic receptors are comprised of at least four types (5-HT/1-4). In the present proposal, the most widely used 5-HT/2-receptor model, the head-twitch response (HTR) in mice, will be utilized to characterize the presynaptic effects of both acute and chronic cocaine administration on the serotonin neuronal system. Recently, the applicant reported that acute cocaine administration dose-dependently attenuates the DOI (a direct 5-HT/2-receptor agonist)-induced HTR, while chronic administration of low doses (0.03-1.25 mg/kg, i.p.Z) of the stimulant enhances the DOI- induced behavior whereas high doses of cocaine has no effect. In the present project the HTR will be produced by the serotonin precursor 5- hydroxytryptophan or the 5-HT releaser d-fenfluramine. These agents will increase the synaptic concentration of 5-HT which will lead to the stimulation of postsynaptic 5-HT/2-receptors and therefore production of HTR. The specific aims of the present protocol are: 1) to determine the presynaptic mechanisms by which acute cocaine administration may modify the HTR produced by the cited inducers. Utilization of specific uptake inhibitors for 5-HT, DA and NE will help to delineate the serotonergic and nonserotonergic effects of cocaine on the induced behavior; 2) to determine the dose- and time-response effects of chronic cocaine exposure on the HTR produced by the cited HTR inducers. These studies will help not only to reveal the acute and chronic effects of cocaine on the 5- HT/2-receptor function but will also show whether cocaine can effect the presynaptic functional and storage pools of 5-HT. These studies are important because acute and chronic cocaine exposure can differentially affect the HTR produced by the direct agonist DOI and by the cited indirect presynaptic mechanisms. Moreover, chronic cocaine exposure may also differentially affect the presynaptic HTR inducers.